KELIM及BRCA突变状态对晚期高级别浆液性卵巢癌中间型肿瘤细胞减灭术预后的影响^*

Effect of Cancer Antigen-125 Elimination Rate Constant K and BRCA Mutation Status on the Prognosis of Interval Debulking Surgery in Advanced High-Grade Serous Ovarian Cancer

摘要

目的 探讨CA125消除速率常数（CA125 elimination rate constant k, KELIM）对接受新辅助化疗联合中间型肿瘤细胞减灭术（neoadjuvant chemotherapy followed by interval debulking surgery，NACT-IDS）的晚期高级别浆液性卵巢癌（high-grade serous ovarian cancer, HGSOC）患者疗效及预后的预测价值，并分析其与乳腺癌易感基因（breast cancer susceptibility gene，BRCA）突变状态的联合预后意义。方法 回顾性纳入106例接受NACT-IDS治疗的晚期HGSOC患者。计算NACT期间的KELIM，以1.0为界分为高、低两组。比较两组临床病理特征、R0切除率及铂敏感率。采用Logistic回归分析R0切除的预测因素，采用Kaplan-Meier法和Cox回归分析无进展生存期（progression free survival，PFS）的影响因素。进一步根据KELIM与BRCA状态进行联合分层，分析各亚组的铂耐药复发风险。结果 KELIM≥1组R0切除率高于KELIM<1组（77.1% vs 55.2%），差异有统计学意义（P=0.024）。多因素Logistic分析显示，KELIM是R0切除的独立预测因子（OR = 2.922，95% CI: 1.112～7.678）。生存分析显示，KELIM≥1组的PFS长于KELIM<1组（33.0个月 vs 18.0个月），差异具有统计学意义（P<0.001）。多因素Cox回归显示，KELIM≥1与PFS进展风险降低相关（HR = 0.481，95% CI: 0.280～0.826）；联合分层分析显示，“KELIM≥1且BRCA阳性”亚组未观察到铂耐药复发（0/21），与KELIM<1且BRCA阴性组相比较，其铂耐药复发风险较低（OR = 0.053，95% CI: 0.003～0.932，P = 0.006）。结论 KELIM是预测NACT-IDS患者手术结局和PFS的有效动态标志物。KELIM与BRCA状态联合分层能更精准地识别铂耐药复发风险极低的“双重有利”人群，为晚期HGSOC的个体化治疗与风险分层管理提供重要依据。

Abstract

Objective To investigate the predictive value of the cancer antigen-125 elimination rate constant K (KELIM) for treatment response and prognosis in patients with advanced high-grade serous ovarian cancer (HGSOC) undergoing neoadjuvant chemotherapy followed by interval debulking surgery (NACT-IDS), and to analyze the combined prognostic significance of KELIM and the mutation status of breast cancer susceptibility gene (BRCA). Methods A total of 106 patients with advanced HGSOC who had undergone NACT-IDS were retrospectively enrolled. The KELIM values during neoadjuvant chemotherapy were calculated, and patients were divided into high- and low-KELIM groups using a cutoff value of 1.0. Clinicopathological characteristics, R0 resection rates, and platinum sensitivity rates were compared between the two groups. Logistic regression analysis was performed to identify predictive factors for R0 resection, while Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to evaluate factors associated with progression-free survival (PFS). Furthermore, the patients were stratified according to both KELIM andBRCA status to assess the risk of platinum-resistant recurrence in each subgroup. Results The R0 resection rate was higher in the KELIM ≥ 1 group than in the KELIM < 1 group (77.1% vs 55.2%), and the difference was statistically significant ( P = 0.024). Multivariate logistic regression analysis showed that KELIM was an independent predictor of R0 resection (odds ratio [OR] = 2.922, 95% CI: 1.112–7.678). Survival analysis demonstrated longer PFS in the KELIM ≥1 group compared with that in the KELIM <1 group (33.0 months vs 18.0 months), and the difference was statistically significant (P < 0.001). Multivariate Cox regression analysis showed that KELIM ≥ 1 was associated with a reduced risk of disease progression (hazard ratio [HR] = 0.481, 95% CI: 0.280-0.826). Combined stratification analysis revealed that no platinum-resistant recurrence was observed in the subgroup with both KELIM ≥1 and a BRCA-positive status (0/21). Compared with patients with KELIM <1 and a BRCA-negative status, this subgroup exhibited a lower risk of platinum-resistant recurrence (OR = 0.053, 95% CI: 0.003-0.932,P = 0.006). Conclusion KELIM is an effective dynamic biomarker for predicting surgical outcomes and PFS in patients undergoing NACT-IDS. Combined stratification by KELIM and BRCA status allows more precise identification of the patient population with both KELIM ≥1 andBRCA-positive status, who have an extremely low risk of platinum-resistant recurrence, thereby providing an important basis for individualized treatment and risk stratification management in patients with advanced HGSOC.

关键词

高级别浆液性卵巢癌 / 中间型肿瘤细胞减灭术 / 新辅助化疗 / CA125消除速率常数K / BRCA基因

Key words

High-grade serous ovarian cancer / Interval debulking surgery / Neoadjuvant chemotherapy / Cancer antigen-125 elimination rate constant K / BRCA gene

参考文献

[1] Gaillard S, Lacchetti C, Armstrong D K, et al. Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: ASCO guideline update[J]. J Clin Oncol, 2025, 43(7): 868. DOI: 10.1200/JCO-24-02589.

[2] Nag S, Ray Coquard I, Gupta S, et al. Pan-asia adapted ESMO clinical practice guideline for the management of patients with newly diagnosed and relapsed epithelial ovarian cancer[J/OL]. ESMO Open, 2025, 10(6): 105125. https://www.esmoopen.com/article/S2059-7029(25)00994-9/fulltext. DOI: 10.1016/j.esmoop.2025.105125.

[3] González-Martín A, Harter P, Leary A, et al. Newly diagnosed and relapsed epithelial ovarian cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up[J]. Ann Oncol, 2023, 34(10): 833. DOI: 10.1016/j.annonc.2023.07.011.

[4] Kim J H, Cho H W, Park E Y, et al. Prognostic value of CA125 kinetics, half-life, and nadir in the treatment of epithelial ovarian cancer: a systematic review and meta-analysis[J]. Int J Gynecol Cancer, 2023, 33(12): 1913. DOI: 10.1136/ijgc-2023-004825.

[5] Zebic D S, Tjokrowidjaja A, Francis K E, et al. Discordance between GCIG CA-125 progression and RECIST progression in the CALYPSO trial of patients with platinum-sensitive recurrent ovarian cancer[J]. Br J Cancer, 2024, 130(3): 425. DOI: 10.1038/s41416-023-02528-z.

[6] You B, Colomban O, Heywood M, et al. The strong prognostic value of KELIM, a model-based parameter from CA 125 kinetics in ovarian cancer: data from CALYPSO trial (a GINECO-GCIG study)[J]. Gynecol Oncol, 2013, 130(2): 289. DOI: 10.1016/j.ygyno.2013.05.013.

[7] Colomban O, Swisher E M, Kristeleit R, et al. Mathematical modeling of the early modeled CA-125 longitudinal kinetics (KELIM-PARP) as a pragmatic indicator of rucaparib efficacy in patients with recurrent ovarian carcinoma in ARIEL2 & STUDY 10[J/OL]. EBioMedicine, 2023, 89: 104477. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00042-7/fulltext. DOI: 10.1016/j.ebiom.2023.104477.

[8] Corbaux P, You B, Glasspool R M, et al. Survival and modelled cancer antigen-125 ELIMination rate constant k score in ovarian cancer patients in first-line before poly (ADP-ribose) polymerase inhibitor era: a gynaecologic cancer intergroup meta-analysis[J/OL]. Eur J Cancer, 2023, 191: 112966. https://www.ejcancer.com/article/S0959-8049(23)00318-0/fulltext. DOI: 10.1016/j.ejca.2023.112966.

[9] Van Wagensveld L, Colomban O, Van der Aa M A, et al. Confirmation of the utility of the CA-125 elimination rate (KELIM) as an indicator of the chemosensitivity in advanced-stage ovarian cancer in a “real-life setting”[J/OL]. J Gynecol Oncol, 2024, 35(3): e34. https://doi.org/10.3802/jgo.2024.35.e34.

[10] Kamm M, Hildebrandt F, Titze B, et al. Ex vivo fluorescence confocal microscopy for intraoperative examinations of lung tumors as alternative to frozen sections: a proof-of-concept study[J/OL]. Cancers (Basel), 2024, 16(12): 2221. https://doi.org/10.3390/cancers16122221.

[11] Ambrosino F A, Pisano C, Napoli M D, et al. KELIM score: a marker of chemosensitivity in ovarian cancer[J/OL]. Cancer Treat Rev, 2026, 143: 103071. https://www.cancertreatmentreviews.com/article/S0305-7372(25)00193-8/abstract. DOI: 10.1016/j.ctrv.2025.103071.

[12] 江珊, 朱靖, 王莹莹, 等. KELIM及BRCA突变状态在预测晚期高级别浆液性卵巢癌预后中的价值[J]. 现代妇产科进展, 2025, 34(3): 185. DOI: 10.13283/j.cnki.xdfckjz.2025.03.031.

[13] Jiang S, Zhu J, Wang Y Y, et al. Evaluating the prognostic value of KELIM and BRCA mutation status in advanced high-grade serous ovarian cancer[J]. Progress in Obstetrics and Gynecology, 2025, 34(3): 185. DOI: 10.13283/j.cnki.xdfckjz.2025.03.031.

[14] St Laurent J, Liu J F. Treatment approaches for platinum-resistant ovarian cancer[J]. J Clin Oncol, 2024, 42(2): 127. DOI: 10.1200/JCO.23.01771.

[15] You B, Robelin P, Tod M, et al. CA-125 ELIMination rate constant k (KELIM) is a marker of chemosensitivity in patients with ovarian cancer: results from the phase Ⅱ CHⅣA trial[J]. Clin Cancer Res, 2020, 26(17): 4625. DOI: 10.1158/1078-0432.CCR-20-0054.

[16] You B, Sehgal V, Hosmane B, et al. CA-125 KELIM as a potential complementary tool for predicting veliparib benefit: an exploratory analysis from the VELIA/GOG-3005 study[J]. J Clin Oncol, 2023, 41(1): 107. DOI: 10.1200/JCO.22.00430.

[17] LI C, CUI Q, WANG X, et al. CA-125 elimination rate constant k (KELIM) as a promising predictor of complete cytoreduction after neoadjuvant chemotherapy in advanced ovarian cancer patients: a retrospective study from two chinese hospitals[J/OL]. BMC Cancer, 2024, 24(1): 609. https://pmc.ncbi.nlm.nih.gov/articles/PMC11107035/. DOI: 10.1186/s12885-024-12252-3.

[18] Bouvarel B, Colomban O, Frenel J S, et al. Clinical impact of CA-125 ELIMination rate constant k (KELIM) on surgical strategy in advanced serous ovarian cancer patients[J]. Int J Gynecol Cancer, 2024, 34(4): 574. DOI: 10.1136/ijgc-2023-004872.

[19] Zouzoulas D, Tsolakidis D, Tzitzis P, et al. The use of CA-125 KELIM to identify which patients can achieve complete cytoreduction after neoadjuvant chemotherapy in high-grade serous advanced ovarian cancer[J/OL]. Cancers (Basel), 2024, 16(7): 1266. https://doi.org/10.3390/cancers16071266.

[20] Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer[J]. N Engl J Med, 2018, 379(26): 2495. DOI: 10.1056/NEJMoa1810858.

[21] Ray-Coquard I, Leary A, Pignata S, et al. Olaparib plus bevacizumab first-line maintenance in ovarian cancer: final overall survival results from the PAOLA-1/ENGOT-ov25 trial[J]. Ann Oncol, 2023, 34(8): 681. DOI: 10.1016/j.annonc.2023.05.005.

基金资助

*国家自然科学基金青年基金(82503869)